rs2075520

Positions:

• chr16-21211351-C-A
• chr16-21211351-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001376232.1(ZP2):​c.107G>T​(p.Gly36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,613,558 control chromosomes in the GnomAD database, including 82,393 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (13043 hom., cov: 31)
  • Exomes 𝑓: 0.30 (69350 hom.)
• Consequence: ZP2 NM_001376232.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.652

Genes affected

ZP2 (HGNC:13188): (zona pellucida glycoprotein 2) The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed of three glycoproteins with various functions during fertilization and preimplantation development. The glycosylated mature peptide is one of the structural components of the zona pellucida and functions in secondary binding and penetration of acrosome-reacted spermatozoa. Female mice lacking this gene do not form a stable zona matrix and are sterile. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.534038E-5).
• BP6: Variant 16-21211351-C-A is Benign according to our data. Variant chr16-21211351-C-A is described in ClinVar as [Benign]. Clinvar id is 3060011.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZP2	NM_001376232.1	c.107G>T	p.Gly36Val	missense_variant	2/19	ENST00000574091.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZP2	ENST00000574091.6	c.107G>T	p.Gly36Val	missense_variant	2/19	1	NM_001376232.1	P1
ZP2	ENST00000574002.1	c.107G>T	p.Gly36Val	missense_variant	3/20	1		P1
ZP2	ENST00000576162.5	n.134G>T		non_coding_transcript_exon_variant	2/9	1
ZP2	ENST00000572752.1	n.119G>T		non_coding_transcript_exon_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58506 AN: 151790 Hom.: 13029 Cov.: 31

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.351 AC: 88217 AN: 251212 Hom.: 17138 AF XY: 0.341 AC XY: 46243 AN XY: 135754

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.445

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.299 AC: 436901 AN: 1461648 Hom.: 69350 Cov.: 45 AF XY: 0.300 AC XY: 217976 AN XY: 727132

Gnomad4 AFR exome AF: 0.620

Gnomad4 AMR exome AF: 0.471

Gnomad4 ASJ exome AF: 0.287

Gnomad4 EAS exome AF: 0.425

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.283

Gnomad4 NFE exome AF: 0.273

Gnomad4 OTH exome AF: 0.311

GnomAD4 genome AF: 0.386 AC: 58566 AN: 151910 Hom.: 13043 Cov.: 31 AF XY: 0.386 AC XY: 28633 AN XY: 74238

Gnomad4 AFR AF: 0.609

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.340

Alfa AF: 0.294 Hom.: 18481

Bravo AF: 0.406

TwinsUK AF: 0.276 AC: 1025

ALSPAC AF: 0.266 AC: 1026

ESP6500AA AF: 0.609 AC: 2677

ESP6500EA AF: 0.279 AC: 2398

ExAC AF: 0.354 AC: 42926

Asia WGS AF: 0.342 AC: 1194 AN: 3478

EpiCase AF: 0.275

EpiControl AF: 0.267

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.68
DANN	Benign	0.086
DEOGEN2	Benign	0.030	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00027	N
MetaRNN	Benign	0.000015	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.1	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.72	T;T
Polyphen		0.0	.;B
Vest4		0.11
MPC		0.073
ClinPred		0.0021	T
GERP RS		2.4
Varity_R		0.035
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2075520; hg19: chr16-21222672; COSMIC: COSV54813198;